Transient Intracellular Acidification Regulates the Core Transcriptional Heat Shock Response

Abstract

Cellular stress induces rapid expression of genes encoding molecular chaperones. Stress also triggers transient intracellular acidification which, by unknown mechanisms, is broadly associated with increased stress resistance in eukaryotes. Here, using budding yeast as a model, we discover that preventing cells from transiently acidifying during heat shock compromises induction of molecular chaperones and fitness. Both acidification and subsequent restoration of intracellular pH are required for robust chaperone induction, with pH recovery and chaperone production predicting resumption of division in single cells. Failure to acidify specifically suppresses genes regulated by the conserved heat shock transcription factor Hsf1, which is repressed by chaperones under non-stress conditions. The failure of heat to induce the heat shock response without concomitant acidification implicates pH-sensitive stress-sensing proteins in recruiting chaperone repressors to activate Hsf1 under physiological conditions. Our findings reveal a central, causal role for intracellular pH in the eukaryotic transcriptional stress response.